Early during their development, embryos can fully compensate for tissue loss: If large parts are removed, the embryos still develop into smaller but complete and healthy organisms. Researchers at the Friedrich Miescher Laboratory of the Max Planck Society in Tübingen wanted to elucidate the underlying molecular mechanism that keeps the tissue proportions constant or “scaled” in differently sized embryos. Together with scientists from Harvard University, they demonstrated that interactions between two molecules, Lefty and Nodal, are key to this scaling mechanism. Their results are presented in the journal Nature Cell Biology.
The observation that embryos of some species still undergo normal development after large tissue blocks have been removed is not new. Researchers had already made this discovery at the beginning of the 19th century, thereby demonstrating that tissue differentiation is controlled by adaptive processes. Today we know that these processes depend on signalling molecules known as “morphogens”.
Zebrafish development imaged by light sheet microscopy. The picture shows the fluorescent nuclei (histones labeled with green fluorescent protein) of all cells.
© Friedrich-Miescher-Laboratorium/Müller, Marcon
However, how morphogens adapt their activity to different conditions – such as different embryo sizes – is not fully understood. Researchers at the Friedrich Miescher Laboratory in Tübingen have now revisited the old developmental biological experiments:
"The motivation for our current work," says Dr. Patrick Müller, the corresponding author of the study published in Nature Cell Biology, "was to address these observations with modern quantitative methods and mathematical modelling to uncover the underlying mechanisms."
The researchers focused on the morphogen “Nodal” and its inhibitor “Lefty”. These two molecules work together to control the formation of the three germ layers (endoderm, mesoderm and ectoderm) during embryonic development. The germ layers roughly correspond to the inside, middle and outside of the embryo, and their establishment is one of the earliest steps in development.
The signal for "inside" is given by Nodal: In the areas where Nodal is most active, cells differentiate into endoderm, while weaker Nodal activity triggers mesoderm formation. When Nodal is suppressed by its inhibitor Lefty, ectoderm forms. This kind of control mechanism is called an “activator-inhibitor” system, and many different systems based on this principle govern a wide range of biological processes.
When large parts of one germ layer are removed, the tissue proportions should be incorrect and development should therefore be disrupted; however, embryos somehow adjust their germ layer proportions and develop just fine.
To see whether the Nodal/Lefty activator-inhibitor system can account for this adjustment, the scientists created smaller zebrafish embryos by removing about one third of their cells, mainly from the ectoderm. Strikingly, the proportions of the germ layers adapted to the embryo’s new size in less than two hours. The distribution of Nodal activity changed even faster, indicating that it is responsible for the adaptive process.
A possible mechanism for how the Nodal/Lefty system can react to such changes was revealed by computer analysis, which took into account all known interactions and molecular properties of Nodal and Lefty. By assessing over 400,000 possible combinations of the unknown properties, the computer program screened for those constellations in which the Nodal/Lefty system could adjust germ layer proportions in response to changes in embryo size.
In such systems, the program revealed, Lefty's concentration needs to increase in smaller embryos. That constrains Nodal signalling further, resulting in reduced endoderm and mesoderm formation and correcting the germ layer proportions.
The researchers experimentally verified this prediction and demonstrated that the model correctly reflected the real process, providing an explanation for a century-old observation. Their results have also drawn attention to a widespread biological principle:
Even in single-celled organisms, similar control processes have been described. Mechanisms that rely on the coupling of overall size to molecule concentrations might therefore be a ubiquitous biological strategy to control growth and differentiation.
Dr. Patrick Müller
Max Planck Research Group “Systems biology of development”
Phone: +49 7071 601-815
Almuedo-Castillo M, Bläßle A, Mörsdorf D, Marcon L, Soh GH, Rogers KW, Schier AF, Müller P (2018). Scale-invariant patterning by size-dependent inhibition of Nodal signalling. Nature Cell Biology, http://dx.doi.org/10.1038/s41556-018-0155-7.
Ann-Kristin Mensendiek | Max-Planck-Institut für Entwicklungsbiologie
Chip-based optical sensor detects cancer biomarker in urine
06.12.2019 | The Optical Society
Scientist identify new marker for insecticide resistance in malaria mosquitoes
06.12.2019 | Liverpool School of Tropical Medicine
University of Texas and MIT researchers create virtual UAVs that can predict vehicle health, enable autonomous decision-making
In the not too distant future, we can expect to see our skies filled with unmanned aerial vehicles (UAVs) delivering packages, maybe even people, from location...
With ultracold chemistry, researchers get a first look at exactly what happens during a chemical reaction
The coldest chemical reaction in the known universe took place in what appears to be a chaotic mess of lasers. The appearance deceives: Deep within that...
Abnormal scarring is a serious threat resulting in non-healing chronic wounds or fibrosis. Scars form when fibroblasts, a type of cell of connective tissue, reach wounded skin and deposit plugs of extracellular matrix. Until today, the question about the exact anatomical origin of these fibroblasts has not been answered. In order to find potential ways of influencing the scarring process, the team of Dr. Yuval Rinkevich, Group Leader for Regenerative Biology at the Institute of Lung Biology and Disease at Helmholtz Zentrum München, aimed to finally find an answer. As it was already known that all scars derive from a fibroblast lineage expressing the Engrailed-1 gene - a lineage not only present in skin, but also in fascia - the researchers intentionally tried to understand whether or not fascia might be the origin of fibroblasts.
Fibroblasts kit - ready to heal wounds
Research from a leading international expert on the health of the Great Lakes suggests that the growing intensity and scale of pollution from plastics poses serious risks to human health and will continue to have profound consequences on the ecosystem.
In an article published this month in the Journal of Waste Resources and Recycling, Gail Krantzberg, a professor in the Booth School of Engineering Practice...
03.12.2019 | Event News
15.11.2019 | Event News
15.11.2019 | Event News
06.12.2019 | Earth Sciences
06.12.2019 | Life Sciences
06.12.2019 | Information Technology